This research proposal describes efforts to elucidate the stereochemistry of drug-nucleic acid intercalative binding by X-ray crystallography. Several of the drugs described (for example, actinomycin and daunomycin) are potent anticancer chemotherapeutic agents, while others (for example, the acridines and their derivatives) are mutagenic and possibly carcinogenic in eukaryotic cells. Understanding the mechanism of action of these drugs may provide greater insight into drug design in future years. We have been able to co-crystallize serveral drugs with DNA-like nucleic acid components. X-ray analyses of these structures has given information directly relevant to understanding their interaction with DNA. Thus, study of an actinomycin-deoxyguanosine crystalline complex has shed light on how actinomycin binds to DNA. The phenoxazone ring system of actinomycin intercalates between the base-paired dinucleotide sequence, dG-dC, while the peptide subunits lie in the narrow groove of the DNA helix and interact with deoxyguanosine residues on opposite chains through specific hydrogen bonds. Recent study of two ethidium-dinucleoside monophosphate crystalline complexes has confirmed the intercalation concept, and these structures have provided additional information of general nature in understanding how ethidium, and a large number of other intercalative drugs, interact with DNA. Current and future research is centered on understanding the stereochemical nature of drug-DNA interactions by X-ray crystallographic analyses of drug-nucleic acid crystalline complexes.